POS0037 MULTIVARIABLE MENDELIAN RANDOMIZATION STUDY ON BMI-ADJUSTED LINK BETWEEN ADIPONECTIN AND RISK OF DEVELOPING RHEUMATOID ARTHRITIS
Authors: G. K. Vasileiadis, T. Fatima, C. Maglio
Journal: Annals of the Rheumatic Diseases (2022)

Background Compelling evidence suggests that adiponectin is involved in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, a recent Mendelian randomization (MR) study in Europeans has shown that adiponectin does not have a causal role in the development of RA 1 . Objectives As body-mass index (BMI) is a known risk factor for RA 2 and subjects with high BMI have lower circulating levels of adiponectin, we specifically aimed to perform a multivariable MR in both European and East Asian populations to determine if adiponectin has a causal effect on RA development independently of BMI. Methods We performed a range of two-sample, univariable, MR analyses to assess the causal effect of adiponectin on RA in European and East Asian individuals. Two different sets (12 in Europeans and 5 in East Asians) of adiponectin-related genetic variants were used as instruments for genetically determined adiponectin levels, to calculate its causal effect on RA risk. Multivariable MR was performed to calculate the effect of adiponectin on RA risk after adjustment for BMI. Results Univariable MR did not provide evidence of a causal relationship between circulating adiponectin levels and RA risk in both European (OR 1.06; 95% CI 0.87-1.31; p=0.59) and East Asian (OR 1.04; 95% CI 0.91 – 1.19; p=0.54) individuals (Figure 1). Similarly, there was no evidence of a causal effect of adiponectin on RA in both European (OR 0.97; 95% CI 0.78 – 1.22; p=0.81) and East Asian (OR 0.97; 95% CI 0.72 – 1.31; p=0.85) populations after adding BMI as a confounder in the multivariable MR model (Figure 1). Figure 1. Forest plot of the causal effects of adiponectin-associated genetic variants on rheumatoid arthritis after adjustment for body mass index in a multivariable mendelian randomization (MR) analysis. Shown are European (EUR) and East Asian (EAS) populations. An Odds Ratio (OR) is a measure of association between an exposure and an outcome, in which the OR represents the likelihood that an outcome will occur given a particular exposure, compared to the likelihood of the outcome occurring in the absence of that exposure. Statistical analyses were performed with the use of inverse-variance weighted (IVW) estimate, MR-Egger regression weighted median analysis. Conclusion This MR study does not support a causal effect of genetically determined adiponectin levels on the risk of developing RA in both European and East Asian populations. By using multivariable MR to account for possible shared genetic predictors between circulating adiponectin levels and BMI we have shown that circulating adiponectin is not causally linked to RA risk after adjustment for BMI. References [1]Chen, H. et al. No Causal Association Between Adiponectin and the Risk of Rheumatoid Arthritis: A Mendelian Randomization Study. Frontiers in Genetics 12, doi:10.3389/fgene.2021.670282 (2021). [2]Bae, S. C. &amp; Lee, Y. H. Causal association between body mass index and risk of rheumatoid arthritis: A Mendelian randomization study. European journal of clinical investigation 49, e13076, doi:10.1111/eci.13076 (2019). Acknowledgements We would like to thank Maria Nethander, Jari Martikainen and Malin Östensson from the Bioinformatics Core Facility at the Sahlgrenska Academy for bioinformatics. We would also like to thank all study participants who agreed to have their DNA used for genetic testing and all the people involved in the study consortia who made their data publicly available. Disclosure of Interests None declared